Stevens-Johnson Syndrome and
Toxic Epidermal Necrolysis
Steven J. Parrillo, DO
Corresponding author
Steven J. Parrillo, DO
Albert Einstein Healthcare Network, Department of Emergency
Medicine, 5501 Old York Road, Philadelphia, PA, 19141, USA.
E-mail: parrills@einstein.edu
Current Allergy and Asthma Reports 2007, 7:243247
Current Medicine Group LLC ISSN 1529-7322
Copyright 2007 by Current Medicine Group LLC
Since their rst descriptions in 1922 and 1948, respec-
tively, Stevens-Johnson syndrome and toxic epidermal
necrolysis (SJS/TEN) have become recognized as mani-
festationswith different severityof the same disease
process along a spectrum of illness. Even today, decades
after their description, there is still disagreement about
when a particular bullous disease evolves from erythema
multiforme to SJS/TEN. There is no disagreement, how-
ever, about the potentially life-threatening nature of the
disease. Many cases are misdiagnosed, especially in
their early stages. In this paper we address our current
understanding of this disease spectrum and discuss both
accepted and more controversial modes of therapy.
Introduction
Stevens-Johnson syndrome (SJS) is an immune complex
mediated hypersensitivity disorder. Although some authors
believe that SJS is a severe expression of erythema multi-
forme, others believe that they are separate diseases. SJS
is also known as erythema multiforme major. Others use
the term erythema multiforme major (or majus) to refer to
severe cases of erythema multiforme major, but differentiate
such cases from Stevens-Johnson syndrome. Contributing
to the confusion, there is also evidence that toxic epidermal
necrolysis (TEN) represents a severe form of SJS, though
some still believe that the two are distinct entities. In this
article, we assume that SJS and TEN are different manifes-
tations of the same disease continuum.
The skin and mucous membranes are the primary
target sites. Significant involvement of oral, nasal, eye,
vaginal, urethral, gastrointestinal (GI), and lower respira-
tory tract mucous membranes may develop in the course
of the illness, though minor presentations may also occur.
GI and respiratory involvement may progress to necrosis.
SJS/TEN is a serious systemic disorder with the potential
for severe morbidity and even death, most commonly due
to sepsis or respiratory complications. Misdiagnosis is
common in the early stage.
History
Stevens-Johnson syndrome was first described in 1922
with the report of two children, ages 7 and 8, who pre-
sented with an extraordinary, generalized eruption with
continued fever, inflamed buccal mucosa and severe puru-
lent conjunctivitis [1]. TEN was first described by Ruskin
in 1948, then again by Lyell in 1956 [2], and was actually
referred to as Lyells syndrome for a time. An associa-
tion between the development of SJS/TEN and drugs has
been established; however, an association with antecedent
infection is less clear.
Pathogenesis
The disorder is thought to develop through an immune
complexmediated hypersensitivity process. It is now
well-recognized that drugs in various categories are
responsible for the development of SJS/TEN. Although
the exact mechanism by which the cascade of events
that lead to the clinical manifestations has not been
fully explained, there are a number of common fea-
tures. Pathologically, apoptotic keratinocyte cell death
causes separation of epidermis from dermis. The death
receptor Fas and its ligand FasL have also been linked
to keratinocyte apoptosis and dermal-epidermal sepa-
ration during TEN [3]. Inflammatory cytokines also
have been implicated [4].
Etiology
Offending agents fall into two broad categories: infections
and drugs. Drug-induced cases far outnumber infection-
associated cases.
Some authors have suggested that infectious cases are
responsible only for erythema multiforme and not SJS.
That controversy notwithstanding, infections that have
been linked to SJS include Mycoplasma pneumoniae,
Yersinia species, and various Herpes species [5,6].
244 Allergic Dermatosis and Urticaria
Figure 1. Toxic epidermal necrolysislesions of mucous membranes.
(From Parrillo and Parrillo [6]; with permission.)
Drugs from several categories have been implicated
in both TEN and SJS [610]. Some authors distinguish
between drugs used on a short-term basis and those used
chronically [8]. In the former group, sulfonamides (especially
trimethoprim-sulfamethoxazole) are the biggest offenders.
Others include aminopenicillins, quinolones, cephalosporins,
and chlormezanone. Presentations of SJS/TEN typically
occur within 3 weeks of drug exposure.
Drugs used on a chronic basis have also been associ-
ated with SJS. These include phenobarbital, phenytoin,
carbamazepine, valproic acid, oxcarbazine, oxicam
nonsteroidal (piroxicam, meloxicam), allopurinol,
and corticosteroids. There have been reports of SJS in
human immunodeficiency virus (HIV)infected patients
treated with the antiretroviral agent nevirapine. Case
reports implicating nevirapine include both patients
with HIV and individuals receiving the agent for post-
exposure prophylaxis [11]. One author suggests that
the problem might extend to other non-nucleoside
reverse transcriptase inhibitors [12]. Even with chronic
medication use, the greatest risk was seen in the first
2 months after drug initiation.
At-risk Populations
Patients who are HIV-positive, especially those with
acquired immunodeficiency syndrome (AIDS), are at
high risk for SJS. Whether the disease is an independent
risk factor or a function of increased likelihood of drug
exposure is still unknown. Intuitively, the latter would
make clinical sense. Some have suggested that patients
in this group may have abnormal patterns of production
or detoxification of drug metabolites; however, other
underlying immunologic abnormalities due to HIV may
also be operative [11].
Infection-associated SJS occurs primarily in children,
with cases reported in patients as young as 3 months.
Children may also develop drug-induced SJS.
Figure 2. Separation of epidermis from dermis in toxic epidermal
necrolysis. (From Parrillo and Parrillo [6]; with permission.)
TEN has been associated with graft-versus-host
reactions in patients who received bone marrow trans-
plantation [13]. Leukemia, lymphoma, ulcerative colitis,
and Crohns disease have also been named as possible risk
factors for TEN [8].
Clinical Presentation
Many patients with SJS/TEN have a prodromal period
lasting up to 2 weeks that may include nonspecific signs
and symptoms such as fever, chills, headache, sore throat,
and malaise. Fever is especially common, occurring in up
to 85%. The typical mucocutaneous lesions then develop
abruptly, and new lesions may continue to develop for a
period of 2 to 4 weeks.
Early lesions are usually erythematous macules
with purpuric centers. Unlike typical erythema mul-
tiforme lesions, these have only two zones of color:
a core, which may be vesicular, purpuric, or necrotic,
and a surrounding area of macular erythema. Some
investigators have called these targetoid in con-
trast to the three-zone target lesions of erythema
multiforme [8]. Early macules may evolve into pap-
ules, vesicles, bullae, or urticarial plaques. The initial
lesions may also appear scarlatiniform. Nikolsky sign
(separation of epidermis from dermis with lateral finger
pressure) may be easily demonstrated. Areas subject to
pressure may demonstrate full detachment (Figs. 13).
The distribution of involved areas may be quite vari-
able. In classic cases, lesions begin on the face and upper
 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Figure 3. Patient with skin sloughing in Stevens-Johnson syndrome.
(From Parrillo and Parrillo [6]; with permission.)
torso, with palms, soles, dorsum of hands, and exten-
sor surfaces most commonly affected [6]. The rash may
be confined to one anatomic area, most often the trunk.
Rash extension usually occurs within 72 hours but may
occur over just a few hours.
Any mucosal surface may be affected. Lesions
include erythema, edema, sloughing, blistering, ulcer-
ation, and necrosis. Oropharyngeal lesions may be
severe, but mucosal involvement may also occur on the
genitalia, esophagus, and tracheobronchial tree. Lower
GI lesions may lead to profuse, protein-rich diarrhea.
Erosive vulvovaginitis or balanitis may produce pain-
ful genitourinary symptoms. It is important to be aware
that internal disease may occur even in the absence of
extensive dermal disease.
Ocular involvement may also occur with potential
long-term sequelae. Corneal lesions and keratitis are com-
mon. Conjunctival erosions may form synechiae in severe
cases, and blindness may develop.
Other signs are seen in association with mucosal and
organ involvement. These may include fever, orthostasis,
tachycardia, hypotension, epistaxis, altered level of con-
sciousness, seizures, and coma.
Classification of Skin Involvement
In 1994 an international group of dermatologists
proposed a system of classification by the degree of epi-
dermal detachment [14]. Five categories were developed to
encompass the spectrum of disease. 1) Bullous erythema
multiformedetachment of less than 10% body sur-
face area (BSA) plus localized typical target lesions or
raised atypical targets. 2) Stevens-Johnson syndrome
detachment of less than 10% BSA plus widespread
erythematous or purpuric macules or flat atypical tar-
gets. 3) Overlap SJS/TENdetachment between 10%
and 30% BSA plus widespread purpuric macules or flat
atypical targets. 4) TEN with spotsdetachment of more
than 30% BSA plus widespread purpuric macules or flat
Parrillo 245
atypical targets. 5) TEN without spotsdetachment of
more than 10% BSA with large epidermal sheets but with-
out purpuric macules or targets.
Others have simplified the classification as follows. SJS
a minor form of TENwould be diagnosed when there is
less than 10% BSA detachment. Overlapping SJS/TEN cases
are represented with detachment of between 10% and 30%,
whereas detachment of more than 30% BSA represents
classic TEN.
Diagnosis
Although the diagnosis is usually clinically apparent,
the differential diagnoses of staphylococcal scalded skin
syndrome and other blistering diseases must be ruled out.
Biopsy of involved areas can provide definitive discrimi-
nation between these processes. Full-thickness epidermal
necrosis is consistent with TEN. Other microscopic fea-
tures include perivascular lymphocyte infiltration [8].
Although no other studies help establish the diag-
nosis, most investigators recommend routine laboratory
studies to include complete blood cell count, creatinine
and electrolyte levels, and cultures as clinically indicated.
Chest radiography should be done when co-existent
pneumonia is suspected. Other diagnostic studies that
may be indicated include bronchoscopy, esophagogas-
troduodenoscopy, and colonoscopy, depending on the
extent of involvement.
Treatment
The primary initial concern is volume status. Fluid replace-
ment follows standard guidelines, such as the Parkland
formula ordinarily used for burn patients. Estimates of
body surface involvement should be done carefully. Large
quantities of saline may be required, but characteristically
less than would be required in a true burn patient with
equivalent BSA involvement. For adults, fluid resuscita-
tion to maintain a urinary flow of 50 to 100 mL/h would
be reasonable. In children, the goal is a flow of approxi-
mately 1 mL/kg/h.
Most authorities strongly advocate transfer to a burn
center if possible, which has been shown to reduce mortal-
ity. Owing to the likelihood that even a case that initially
appears minor and benign may evolve quickly, many advo-
cate hospitalization for all patients with SJS/TEN [8].
Protein loss can be significant. Nutritional support
is critical, and the patient may require parenteral or
enteral hyperalimentation.
Whether treated at a burn center or another type of
facility, sterile wound care is also critical. Most authorities
believe that necrotic tissue must be debrided regularly and
replaced with biologic grafts or porcine xenografts. Oth-
ers leave necrotic intact epidermis in place. One commonly
used topical burn treatmentsilver sulfadiazinemust
be avoided because of its sulfa base.
246 Allergic Dermatosis and Urticaria
Although most authors believe that antibiotics
should only be used for specific infectious complications,
others disagree and recommend prophylactic antibiot-
ics after obtaining cultures in patients with extensive
involvement [15,16].
An ophthalmologist should see all patients with
SJS/TEN. Selected patients should also be seen in con-
sultation by a pulmonologist and/or a gastroenterologist
if involvement of these organ systems is suspected.
Withdrawal of suspected offending drugs is criti-
cal. Doing so earlier rather than later has been shown to
decrease mortality rate [17].
Although to date there have been no randomized
controlled trials of corticosteroid use, most uncontrolled
studies have shown an increased rate of sepsis-related
death. It should be noted that although both treated and
nontreated patients develop sepsis, those receiving steroids
are more likely to die [18].
Most studies show a benefit from the administration
of intravenous immune globulin (IVIg). The rationale
proposes that IVIg blocks target cell death via a receptor-
ligand blocking antibody present in pooled human IVIg
[3,4]. In an opposing view based on a small prospec-
tive study, Bachot et al. [19] stated that their results
do not support the routine use of IVIg treatment for
patients with SJS or TEN, especially in cases of impaired
renal function.
In a small uncontrolled study of severe TEN cases
(BSA 83% 17%), Arevalo et al. [20] showed that
patients benefited from cyclosporine when compared
with historical controls who received cyclophosphamide
and steroids. Given the poorer prognosis in patients
receiving steroids, the perceived benefit from cyclospo-
rine is uncertain.
Mortality
Generally speaking, the mortality rate is determined
largely by the extent of skin sloughing [3,8], as follows:
less than 10% BSA, 1% to 5%; greater than 30% BSA,
25% to 35%.
The SCORTEN (ie, score for TEN) is a severity-
of-illness score, calculated within the first 24 hours of
admission [21]. Each feature is assigned one point. The
total is the SCORTEN number. Variables include age
older than 40 years; presence of malignancy; heart rate
greater than 120; initial percentage of skin detachment
greater than 10% BSA; blood urea nitrogen (BUN)
greater than 10 mmol/L (27 mg/dL); serum glucose
greater than 14 mmol/L (252 mEq/L); and bicarbonate
less than 20 mmol/L (20 mEq/L).
Mortality based on SCORTEN number is as fol-
lows: 0 to 1, 3.2%; 2, 12.1%; 3, 35.3%; 4, 58.3%; 5 or
higher, 90%.
Conclusions
Stevens-Johnson syndrome and toxic epidermal necrol-
ysis most likely represent different degrees of severity
of the same disease process. Skin and mucous mem-
branes are the primary targets. Early diagnosis and
management are key to positive outcomes. Referral to a
burn center is warranted if such facilities are available.
Fluids and maintenance of nutritional status represent
the mainstays of early management. Although still
somewhat controversial, many advocate use of IVIg,
and cyclosporine is also commonly used. Most avoid
corticosteroids because of an attendant increased risk
of infection. Careful assessment of the extent of epider-
mal detachment and other clinical features can provide
important early prognostic information. Mortality
remains high in patients who have significant areas of
skin involvement, with death usually resulting from
sepsis or airway compromise.
References and Recommended Reading
Papers of particular interest, published recently,
have been highlighted as:
Of importance
Of major importance
1. Stevens AM, Johnson FC: A new eruptive fever associated
with stomatitis and ophthalmitis. Report of two cases in
children. Am J Dis Child 1922, 526533.
2. Browne BJ, Rogers RL: Dermatologic emergencies. Prim Care
2006, 33:685695, vi.
3. French LE, Trent JT, Kerdel FA: Use of intravenous
immunoglobulin in toxic epidermal necrolysis and
Stevens-Johnson syndrome: our current understanding.
Int Immunopharmacol 2006, 6:543549.
The authors review their own experience as well as that of others in
their recommendation to use IVIg.
4. French LE: Toxic epidermal necrolysis and Stevens-Johnson
syndrome: our current understanding. Allergol Int 2006,
55:916.
French, one of the authors of reference 3, extensively discusses
current thoughts about pathophysiology and rationale for IVIg
therapy. He also reviews distinctions between SJS and TEN, and
covers mortality.
5. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al.: SCAR
Study Group. Severe Cutaneous Adverse Reactions: Correla-
tions between clinical patterns and causes of erythema
multiforme majus, Stevens-Johnson syndrome, and toxic
epidermal necrolysis: results of an international prospective
study. Arch Dermatol 2002, 138:10191024.
6. Parrillo SJ, Parrillo CV: Stevens-Johnson syndrome. eMedicine
Journal 2006, 7:112. Available at: www.eMedicine.com.
Accessed December 2006.
7. Chan HL, Stern RS, Arndt KA, et al.: The incidence of
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toxic epidermal necrolysis. A population-based study with
particular reference to reactions caused by drugs among
outpatients. Arch Dermatol 1990, 126:4347
8. Klein PA: Stevens-Johnson Syndrome and Toxic Epidermal
Necrolysis. eMedicine Journal 2006, 7:115. Available at:
www.emedicine.com. Accessed December 2006.
9. Roujeau JC, Kelly JP, Naldi L, et al.: Medication use and
the risk of Stevens-Johnson syndrome and toxic epidermal
necrolysis. N Engl J Med 1995, 333:16001607.
 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
10. Strom BL, Carson JL, Halpern AC, et al.: A population-based
study of Stevens-Johnson syndrome. Incidence and antecedent
drug exposures. Arch Dermatol 1991, 127:831838.
11. Todd G: Adverse cutaneous drug eruptions and HIV:
a clinicians global perspective. Dermatol Clin 2006,
24:459472.
The association between drug eruptions and the at-risk HIV popu-
lation has received a good deal of press in recent years. This paper
discusses not only SJS/TEN but also other adverse drug reactions.
12. Metry DW, Lahart CJ, Farmer KL, et al.: Stevens-Johnson
syndrome caused by the antiretroviral drug nevirapine.
J Am Acad Dermatol 2001, 44:354357.
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and toxic epidermal necrolysis: a clinical classification.
J Invest Dermatol 1994, 102:28S30S.
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Johnson syndrome and toxic epidermal necrolysis: a review
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94:419436.
An authoritative, well-referenced review of the literature. It is also
one of two references included here that attempt to make a case for
prophylactic antibiotics.
Parrillo 247
16. Chave TA, Mortimer NJ, Sladden MJ, et al.: Toxic
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withdrawal of causative drugs decrease the risk of death?
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18. Halebian PH, Corder VJ, Madden MR, et al.: Improved
burn center survival of patients with toxic epidermal
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204:503512.
19. Bachot N, Revuz J, Roujeau JC: Intravenous immuno-
globulin treatment for Stevens-Johnson syndrome and
toxic epidermal necrolysis: a prospective noncomparative
study showing no benefit on mortality or progression.
Arch Dermatol 2003, 139:3336.
20. Arevalo JM, Lorente JA, Gonzalez-Herrada C, et al.: Treat-
ment of toxic epidermal necrolysis with cyclosporine A.
J Trauma 2000, 48:473478.
21. Bastuji-Garin S, Fouchard N, Bertocchi M, et al.: SCORTEN:
a severity-of-illness score for toxic epidermal necrolysis.
J Invest Dermatol 2000, 115:149153.
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